Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. It is anticipated that more than a million new cancer cases will be diagnosed in 2008 in the United States alone. Additionally, more than a half a million Americans are expected to die of cancer during the year 2008, and cancer is exceeded only by heart disease as the most common cause of death in the United States. Cancer Facts & Figures 2008, The American Cancer Society (2008). Therefore, there is a need for additional treatment compounds, strategies, and regimens to address this significant medical problem in the United States and around the world.
Many cancer patients also suffer from drug resistance. In other words, the chemotherapeutic drugs that they have been taking for treatment of their cancer cease to work when the cancer becomes resistant to the drug. Often times, resistance to one drug also generates resistance to other drugs because of commonalities in the mechanisms of action between drugs. This, of course, increases the problems faced by the patient as not only is the drug they were taking ineffective, but other drugs are now ineffective as well. This is termed multidrug resistance. Thus, while many cancer treatments exist currently, there is always a need for more treatment options, especially those that do not have cross resistance when a patient becomes resistant to another initial treatment.
Multiple cancer chemotherapy agents exist in the prior art; however, for the reasons identified, they are insufficient. A large number of synthetic compounds or naturally occurring products contain two reactive nucleophilic centers in the molecule. These compounds often exhibit potent antitumor activity since they can covalently bind to DNA. The synthetic N-mustards (Palmer B D et al., J. Med. Chem. 1990, 33, 112-121), which contain N,N-bis(2-chloroethyl)amine active pharmacophore and cis-platinum complexes (Kasparkova J. et al., Biochemistry 1999, 38, 10997-10005; Kloster M et al., Biochemistry, 2004, 43, 7776-7786) have been the most widely used DNA-interstrand cross-linking agents. Due to their abilities to damage DNA molecules, many antitumor N-mustards are currently used clinically for cancer chemotherapy (Hansson J. Cancer Res. 1987, 47, 2631-2637). For instance, the antibiotic anticancer mitomycin C (MMC, 1, FIG. 1) (Tomasz M et al., Pharmacol. Ther., 1997, 76, 73-87; Doll C D et al., J. Clin. Oncol. 1984, 3, 276-286; Satorelli A C, Cancer Res. 1988, 48, 775-778) and its analogue, indoloquinone EO9 (2), (Oostveen E A et al., Tetrahedron 1987, 43, 255-262), which are bifunctional alkylating agents that are able to cross-link to DNA double strands after bioreductive activation (Carter S K et al., Mitomycin C: Current Status and New Developments; Academic Press: New York, 1979). Another class of dialkylating agents, bis(hydroxymethyl)pyrrolizidines and the corresponding bis(carbamates), have certain similarities with mitomycins. The “vinylogoues carbinolamines,” such as thioimidazoles (carmethizole, 3)(Anderson W K et al., J. Med. Chem. 1989, 32, 119-127; Elliot W L et al., Cancer Res. 1991, 51, 4581-4587) 2,3-dihydroxy-6,7-bis(hydroxymethyl)-1H-pyrrolizine[4 (IPP), 5, and 6, FIG. 1] (Anderson W K et al., Arzneim. Forsch. 1980, 30, 765-768; Anderson W K et al., J. Med. Chem. 1977, 20, 812-818) and bis-alcohols 7, were developed initially from the pyrrolizine alkaloids as DNA alkylators. Among these agents, the bis(carbamates) derivatives exhibited significant antitumor activity and afforded “cures” at low dose in the in vivo P-388 assay (Anderson W K et al., J. Med. Chem. 1977, 20, 812-818). These derivatives are capable of forming an interstrand cross-link with the short oligonucleotide 5′-ACGT at the 5′-CG residues at the minor groove region (Woo J et al., J. Am. Chem. Soc. 1993, 115, 3407-3415).
The mechanism of action of bis(carbamate)pyrroles or pyrrolizines was proposed to be able to cross-link with DNA doubled strands via SN1 electrophilic reaction (Anderson W K et al., J. Med. Chem. 1977, 20, 812-818; Woo J et al., J. Am. Chem. Soc. 1993, 115, 3407-3415). It is speculated that the potential electrophilic reactivity in these agents (via O-alkyl cleavage) can be enhanced by participating the lone pair electron on the ring nitrogen similar to that of MMC derivatives. In other words, it might be possible to affect the cytotoxicity of these congeners by inducing the electronic effects through the substituted phenyl groups at C2 of pyrroles or C5 of pyrrolizines. However, it was reported that the in vivo antileukemic activity and the host toxicity were not altered to a considerable degree as a function of electronic properties of phenyl substituent probably due to the insignificance of the electronic effects (Anderson W K et al, J. Med. Chem. 1984, 27, 1321-1325; Anderson W K et al., J. Med. Chem. 1979, 22, 977-980).
In contrast with pyrrole derivatives, the C-5-phenyl and the pyrrole ring in 5-phenylpyrrolizine are coplanar. Studies on the structure-activity relationships of 5-phenylpyrrolizines revealed that compounds having electron-donating substituents on the phenyl ring were generally more toxic than compounds bearing electron-withdrawing substituents, while the in vivo antitumor activities were comparable or slightly less potent in compounds having an electron-donating substituent (Anderson W K et al., J. Med. Chem. 1983, 26, 1333-1338; Anderson W K et al., J. Med. Chem. 1982, 25, 84-86). These studies suggested that the lipophilicity of compound might also affect its antitumor potency.
It is accordingly a primary object of the invention to disclose a series of newly synthesized compounds that posses potent antitumor therapeutic efficacy. Specifically, the present inventors synthesized a series of bis(hydroxymethyl) of 8-H-3a-azacyclopenta[a]indene and 5,10-dihydropyrrolo[1,2-b]isoquinolines derivatives (Formula I and III, respectively) and their corresponding biscarbamates (Formula II and IV, respectively), which can be considered as “benzologues” of pyrrolizines, for antitumor studies.
These agents were subjected to antitumor studies. The results showed that these compounds could exhibit significant cytotoxicity in inhibiting various human tumor cell growth in vitro and could possess potent therapeutic efficacy in animal bearing human tumor xenografts (such as human breast carcinoma MX-1 and lung carcinoma HCT-116). The results demonstrated these compounds could possess potent antitumor therapeutic efficacy and have potential for clinical applications.